Adrenomedullin Signaling at the Maternal-Fetal Interface

 描述(申请人提供)：肾上腺髓质素(AM)是一种多功能多肽，参与多种生物学过程，包括胚胎发育、血管生成、心脏保护和先天免疫。在正常妊娠期间，母体血浆AM水平显著升高，但异常低的水平往往与各种妊娠并发症有关，包括先兆子痫、胎儿生长受限、妊娠期糖尿病和自然流产。利用基因工程小鼠模型，我们的实验室首次证明了母体AM单倍体不足会导致与异常着床和胎儿生长受限相关的大量生殖缺陷。我们还揭示了胎儿来源的AM是母体螺旋动脉适当重塑所必需的--这是怀孕期间胎儿与母体沟通的重要性的新证明。总而言之，我们的研究表明，AM肽在母胎界面的剂量和信号是确保正常妊娠和分娩的一个重要方面。因此，我们打算在这些发现的基础上提出问题：“AM的剂量是如何以及为什么在母胎界面得到精确调节的？”使用复杂的小鼠遗传模型以及体外药理学和细胞生物学测试，我们计划从三个不同的目标来解决这个广泛的问题。在特定的目标1中，我们将检验这一假说，即新鉴定的诱骗趋化因子受体CXCR7在早期着床和胎盘形成过程中作为AM介导的活动的“生物变阻器”。《特殊目的2》将验证这样一种假设，即胎儿滋养层细胞中AM基因表达的剂量是由一组离散的细胞固有miRNAs平衡的，这些miRNAs是由母体因素(如怀孕激素)和环境因素(如吸烟)诱导的。在具体目标3中，我们将进一步阐明AM影响螺旋动脉(SA)重构的不同细胞过程和分子机制。我们的研究结果将进一步加深我们对控制胎盘中母胎沟通的分子和过程的基本理解，并有可能为改善妊娠并发症提供新的临床诊断工具和治疗方法。

 DESCRIPTION (provided by applicant): Adrenomedullin (AM) is a multifunctional peptide that is involved in a variety of biological processes, including embryonic development, angiogenesis, cardio-protection, and innate immunity. Maternal plasma levels of AM rise substantially during a normal pregnancy, but abnormally low levels are often associated with a variety of pregnancy complications including preeclampsia, fetal growth restriction, gestational diabetes and spontaneous abortion. Using genetically engineered mouse models, our laboratory was the first to demonstrate that haploinsufficiency for maternal AM causes a multitude of reproductive defects associated with abnormal implantation and fetal growth restriction. We also revealed that fetal-derived AM is required for the appropriate remodeling of maternal spiral arteries-a novel demonstration of the importance of fetal-to-maternal communication during pregnancy. Collectively our studies have shown that the dosage and signaling of AM peptide at the maternal-fetal interface is an essential aspect to ensuring a normal pregnancy and birth. Therefore, we intend to build on these findings by asking: "How and why does the dosage of AM get precisely regulated at the maternal-fetal interface?" Using sophisticated genetic mouse models and in vitro pharmacological and cell biological assays, we plan to address this broad question in three discrete Aims. In Specific Aim 1, we will test the hypothesis that the newly characterized decoy chemokine receptor, CXCR7, acts as a "biological rheostat" for AM-mediated activity during early implantation and placentation. Specific Aim 2 will test the hypothesis that the dosage of AM gene expression in fetal trophoblast cells is balanced by a discrete subset of cell-intrinsic miRNAs that are induced by maternal factors such as pregnancy hormones and environmental factors, like cigarette smoke. In Specific Aim 3 we will further elucidate the distinct cellular process and molecular mechanisms that govern the effects of AM on spiral artery (SA) remodeling. Results from our studies will further our basic understanding of molecules and processes that govern maternal- to-fetal communication in the placenta and have the potential of providing new clinical diagnostic tools and therapeutic approaches for the amelioration of complications of pregnancy.